1. Field of the Invention
The present invention relates to retroviral protease inhibitors and, more particularly relates to novel compounds and a composition and method for inhibiting retroviral proteases. This invention, in particular, relates to cyclic sulfone moiety-containing hydroxyethylamine protease inhibitor compounds, a composition and method for inhibiting retroviral proteases such as human immunodeficiency virus infection. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
2. Related Art
During the replication cycle of retroviruses, gag and gag-pol gene products are translated as proteins. These proteins are subsequently processed by a virally encoded protease (or proteinase) to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. It has been shown that correct processing of the precursor proteins by the retroviral protease is necessary for assembly of infectious virons. For example, it has been shown that frameshift mutations in the protease region of the pol gene of HIV prevents processing of the gag precursor protein. It has also been shown through site-directed mutagenesis of an aspartic acid residue in the HIV protease that processing of the gag precursor protein is prevented. Thus, attempts have been made to inhibit viral replication by inhibiting the action of retroviral proteases.
Retroviral protease inhibition typically involves a transition-state mimetic whereby the retroviral protease is exposed to a mimetic compound which binds (typically in a reversible manner) to the enzyme in competition with the gag and gag-pol proteins to thereby inhibit replication of structural proteins and, more importantly, the retroviral protease itself. In this manner, retroviral proteases can be effectively inhibited.
Several classes of mimetic compounds are known to be useful as inhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198; G.B. 2,184,730; G.B. 2,209,752; EPO 264 795; G.B. 2,200,115 and U.S. SIR H725; and U.S. Pat. No. 4,599,198 disclose urea-containing hydroxyethylamine renin inhibitors. However, it is known that, although renin and HIV proteases are both classified as aspartyl proteases, compounds which are effective renin inhibitors generally cannot be predicted to be effective HIV protease inhibitors.
Several classes of mimetic compounds have been proposed, particularly for inhibition of proteases, such as for inhibition of HIV protease. Such mimetics include hydroxyethylamine isoteres and reduced amide isosteres. See, for example, EPO 346 847; EPO 342,541; Roberts et al, xe2x80x9cRational Design of Peptide-Bases Proteinase Inhibitorsxe2x80x9d, Science, 248, 358 (1990); and Erickson et al, xe2x80x9cDesign Activity, and 2.8xc3x85 Crystal Structure of a C2 Symmetric Inhibitor Complexed to HIV-1 Proteasexe2x80x9d, Science, 249, 527 (1990). EPO 346 847 discloses certain N-heterocyclic moiety-containing hydroxyethylamine protease inhibitor compounds, but does not suggest or disclose those of the present invention.
Dipeptide isosteres as inhibitors of HIV protease are found in EP application numbers 91309292, 91309028.8 and 91309302.7.
The present invention is directed to virus inhibiting compounds and compositions. More particularly, the present invention is directed to retroviral protease inhibiting compounds and compositions, to a method of inhibiting retroviral proteases, to processes for preparing the compounds and to intermediates useful in such processes. The subject compounds are characterized as cyclic sulfone- and either urea- or N-heterocyclic moiety-containing hydroxyethylamine inhibitor compounds.
In accordance with the present invention, there are provided novel retroviral protease inhibiting compounds or a pharmaceutically acceptable salt, prodrug or ester thereof.
Generally, the present invention is a compound of the formula (Ixe2x80x3) 
and a pharmaceutically acceptable salt, prodrug or ester thereof; wherein Q, R2 and R6 are as defined below and
W represents 
wherein Yxe2x80x2 is as defined below; and
t represents 0,1 and 2, preferably 1;
txe2x80x2 represents 1 and 2, preferably 1;
u represents 0, 1 and 2;
R40, R41, R42, R43, R48, R49, R50 and R51 independently represent hydrogen and alkyl;
R44, R45, R46, R47 and independently represent hydrogen, alkyl and hydroxy; or
one of (a) R40 together with R48, (b) R43 together with R45, (c) R45 together with R47, and (d) R47 together with R48 represent a bond; or
one of (a) R44 together with R45, (b) R46 together with R47 or (c) R50 together with R51 represent a double bond oxygen.
R40 through R48 most preferably represent hydrogen, however, both R46 and R47 also preferably represent methyl at the same time R40 through R45 and R48 are all hydrogen. Additionally, R48 is preferably hydrogen and the stereo configuration of the carbon to which R48 is attached is preferably in the configuration represented by the upper spot in Example 4 set forth hereinafter, and preferably wherein the stereochemistry about the hydroxy group may be designated as (R).
Thus, the present invention compound is preferably of the formula (Ixe2x80x2) 
or a pharmaceutically acceptable salt, prodrug or ester thereof; and wherein Q is: 
and wherein t, Yxe2x80x2, R6, R2, Y, R3, X, R4, R5, R4xe2x80x2 and R5xe2x80x2 are as defined below, q represents 1 or 2;
R4xe2x80x3, R9 and R9xe2x80x2 independently represent radicals as defined by R3;
n represents 0 to 6;
R7 and R7xe2x80x2 independently represent radicals as defined for R3 and amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, alloisoleucine, asparagine, leucine, glutamine, and t-butylglycine or R7 and R7xe2x80x2 together with the carbon atom to which they are attached form a cycloalkyl radical;
R8 represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals and radicals represented by the formulas C(O)R16, CO2R16, SO2R16, SR16, CONR16R17, CF3 and NR16R17;
wherein R16 and R17 independently represent hydrogen and radicals as defined for R3, or R16 and R17 together with a nitrogen to which they are attached in the formula NR16R17 represent heterocycloalkyl and heteroaryl radicals.
A more preferred class of retroviral inhibitor compounds of the present invention are those represented by the formula (I) 
or a pharmaceutically acceptable salt, prodrug or ester thereof, and wherein:
t represents either 0, 1 or 2;
R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, which radicals are optionally substituted with a substituent selected from the group consisting of alkyl and halogen radicals, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3, xe2x80x94OR9, xe2x80x94SR9, wherein R9 represents hydrogen and alkyl radicals;
R3 represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl; heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical, thioalkyl, alkylthioalkyl, and arylthioalkyl radicals and the sulfone or sulfoxide derivatives thereof;
Y and Yxe2x80x2 independently represent O, S and NR15 wherein R15 represents hydrogen and radicals as defined for R3;
X represents N, CH or O;
R4 and R5 independently represent hydrogen and radicals as defined by R3, or when X represents N, R4 and R5 together with the nitrogen atom to which they are bonded represent heterocycloalkyl and heteroaryl radicals, or when X represents CH, R4 and R5 together with the carbon atom to which they are bonded represent a cycloalkyl radical with the proviso R5is nothing when X is O;
R6 represents hydrogen and alkyl radicals;
The compound of the formula I preferably includes a compound wherein Y and Yxe2x80x2 represent O, R6 represents hydrogen, t represents 1 and X represents N.
Another compound of the formula I preferably includes a compound wherein R2 represents benzyl, cyclohexylmethyl, n-butyl, 2-naphthylmethyl, p-fluorobenzyl and isobutyl.
Another compound of the formula I preferably includes a compound wherein R4 and R5 independently represent hydrogen, methyl, ethyl, isopropyl and tertiary-butyl.
Another compound of the formula I preferably includes a compound wherein R4 and R5 together with the nitrogen to which they are attached represent a 5 to 8 membered heterocycloalkyl ring.
And finally, another compound of the formula I preferably includes a compound wherein R3 is isobutyl, n-butyl, isoamyl, benzyl, p-fluorobenzyl and cyclohexylmethyl.
Another more preferred class of retroviral inhibitor compounds of the present invention are those represented by the formula (II) 
or a pharmaceutically acceptable salt, prodrug or ester thereof, and wherein:
t, R2, Yxe2x80x2, and R6 represent radicals as defined above; and
R4xe2x80x2 and R5xe2x80x2 together with the nitrogen atom to which they are bonded represent an N-heterocyclic moiety.
A compound of the formula II preferably includes a compound wherein Yxe2x80x2 represents O, t represents 1 and R6 represents hydrogen.
Another compound of the formula II preferably includes a compound wherein R2 represents benzyl, p-fluorobenzyl, cyclohexylmethyl, 2-naphthylmethyl, n-butyl and isobutyl.
Another compound of the formula II preferably includes a compound wherein NR4xe2x80x2R5xe2x80x2 represents 2-[[(1,1-dimethylethyl)amino]carbonyl]decahydroisoquinolinyl- or 2-[[(1,1-dimethylethyl)amino]carbenyl]piperidinyl.
Another more preferred class of retroviral inhibitor compounds of the present invention are those represented by the formula (III) 
or a pharmaceutically acceptable salt, prodrug or ester thereof, and
wherein t, Yxe2x80x2, R6, R2 and R3 represent radicals as defined above; and
q represents 1 or 2; and
R4xe2x80x3 represents radicals as independently defined by R3.
A compound of the formula III preferably includes a compound wherein Yxe2x80x2 represents O, t represents 1, R6 represents hydrogen and q represents 2.
Another compound of the formula III preferably includes a compound wherein R2 represents benzyl, p-fluorobenzyl, 2-naphthylmethyl, cyclohexylmethyl, n-butyl and isobutyl.
Another compound of the formula III preferably includes a compound wherein R3 represents isobutyl, n-propyl, n-butyl, isoamyl, cyclohexylmethyl and cyclohexyl.
Another compound of the formula III preferably includes a compound wherein R4xe2x80x3 represents an aryl or heteroaryl radical.
Another compound of the formula III preferably includes a compound wherein R4xe2x80x3 represents a para-substituted phenyl wherein the substituent is hydrogen, fluoro, chloro, bromo, nitro, hydroxy, methoxy and amino.
Other more preferred classes are as follows: 
or a pharmaceutically acceptable salt, prodrug or ester thereof;
wherein t, Yxe2x80x2, R6, R2, R3, Y, q, R4, R5, R7, R7xe2x80x2, n and R8 are as defined above.
A compound of the formula IV preferably includes a compound wherein Yxe2x80x2 represents O, R6 represents hydrogen and q represents 2.
Another compound of the formula IV preferably includes a compound wherein R2 represents benzyl, p-fluorobenzyl, 2-naphthylmethyl, n-butyl, cyclohexylmethyl and isobutyl.
Another compound of the formula IV preferably includes a compound wherein R3 represents isobutyl, n-propyl, n-butyl, isoamyl, cyclohexylmethyl and cyclohexyl.
Another compound of the formula IV preferably includes a compound wherein R4 and R5 independently represent hydrogen, methyl, ethyl, isopropyl, t-butyl, phenyl and cyclohexyl or wherein R4 and R 5 and the nitrogen to which they are attached represent a 5 to 8 membered heterocycloalkyl ring.
A compound of the formula V preferably includes a compound wherein Yxe2x80x2 represents O, R6 represents hydrogen, t represents 1, and q represents 2.
Another compound of the formula V preferably includes a compound wherein R2 represents benzyl, p-fluorobenzyl, 2-naphthylmethyl, cyclohexylmethyl, n-butyl, and iso-butyl.
Another compound of the formula V preferably includes a compound wherein R3 represents isobutyl, n-propyl, n-butyl, isoamyl, cyclohexylmethyl and cyclohexyl.
A compound of the formula VI preferably includes a compound wherein Y and Yxe2x80x2 both represent O, R6 represents hydrogen and t represents 1.
Another compound of the formula VI preferably includes a compound wherein R2 represents benzyl, p-fluorobenzyl, 2-naphthylmethyl, cyclohexylmethyl, n-butyl, and isobutyl.
Another compound of the formula VI preferably includes a compound wherein R3 represents isobutyl, n-propyl, isoamyl, n-butyl, cyclohexylmethyl, benzyl, p-fluorobenzyl and p-methoxybenzyl.
Another compound of the formula VI preferably includes a compound wherein R7 and R7xe2x80x2 independentyly represent hydrogen, methyl and ethyl, or together with the carbon to which they are attached represent a 3 to 6 membered cycloalkyl ring.
The most preferred compounds of the present invention are those of the formula I through VI wherein t is 1, R6 is hydrogen, and R2 is an aralkyl, alkyl or cycloalkylalkyl radical.
Each of the compounds of the present invention is represented by formula having at least three optically active carbon centers. The present invention is meant to include compounds having each of the combinations of optical rotation and mixtures thereof. The present compounds may have additional stereoisomers and thus is also meant to include each of such isomers.
In each of the Formula I, II, III, IV, V, and VI a preferred structure is one where stereo configuration of the group xe2x80x94C(OH)xe2x80x94 shown by the OH on the carbon adjacent the carbon having R2 attached is represented by the stereochemistry designated as (R).
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to about 10, preferably from 1 to about 8, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like. The term xe2x80x9cthioalkylxe2x80x9d means aralkyl radical having at least one sulfur atom, wherein alkyl has the significance given above. An example of athioalkyl is xe2x80x94C(CH3)2SCH3. The corresponding sulfoxide and sulfone of this thioalkyl are xe2x80x94C(CH3)2S(O)CH3 and xe2x80x94C(CH3)2S(O)2CH2, respectively. The term xe2x80x9calkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to about 18 carbon atoms preferably from 2 to about 8 carbon atoms. Examples of suitable alkenyl radicals include ethenyl, propenyl, alyl, 1,4-butadienyl and the like. The term xe2x80x9calkynylxe2x80x9d, alone or in combination, mans a straight-chain hydrocarbon radical having one or more triple bonds and containing from 2 to about 10 carbon atoms. Examples of alkynl radicals include ethynyl, propynyl (propargyl), butynyl and the like. The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, means an alkyl radical which contains from about 3 to about 8 carbon atoms and is cyclic. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyciohexyl and the like. The term xe2x80x9ccycloalkylalkylxe2x80x9d means an alkyl radical as defined above which is substituted by a cycloalkyl radical containing from about 3 to about 8, preferably from about 3 to about 6, carbon atoms. The term xe2x80x9carylxe2x80x9d, alone or in combination, means a phenyl or naphthyl radical which optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-hydroxyphenyl, l-naphthyl, 2-naphthyl, and the like. The term xe2x80x9caralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is benzyl, 2-phenylethyl and the like. The term xe2x80x9caralkoxy carbonylxe2x80x9d, alone or in combination, means a radical of the formula xe2x80x94C(O)xe2x80x94O-aralkyl in which the term xe2x80x9caralkylxe2x80x9d has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl. The term xe2x80x9caryloxyxe2x80x9d, alone or in combination, means a radical of the formula aryl-Oxe2x80x94 in which the term xe2x80x9carylxe2x80x9d has the significance given above. The term xe2x80x9calkanoylxe2x80x9d, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. The term xe2x80x9ccycloalkylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term xe2x80x9caralkanoylxe2x80x9d means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-phenylbutyryl, (1-naphthyl)acetyl, derived from a monocylic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid which is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term xe2x80x9caralkanoylxe2x80x9d means an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-phenylbutyryl, (1-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, and the like. The term xe2x80x9caroylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like. The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclylalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heteroycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulphur, which is optionally substituted on one or more carbon atoms by halogen alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (i.e., + Nxe2x80x94) by oxido and which is attached via a carbon atom. The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, or heteroaralkoxycarbonyl group or the like is an aromatic monocyclic, bicyclic, or tricyclic heterocycle which contains the hetero atoms and is optionally substituted as defined above with respect to the definition of heterocyclyl. Examples of such heterocyclyl and heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl etc.), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl (e.g., 2-indolyl, etc.), quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, etc.), tetra hydroquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxoisoquinolinyl, etc), quinoxalinyl, beta-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4-, or 5-benzimidazolyl, and the like. The term xe2x80x9ccycloalkylalkoxycarbonylxe2x80x9d means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-Oxe2x80x94COOH wherein cycloalkylalkyl has the significance given above. The term xe2x80x9caryloxyalkanoylxe2x80x9d means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclylalkanoylxe2x80x9d is an acyl radical derived from a heterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl has the significance given above. The term xe2x80x9cheterocyclyloxycarbonylxe2x80x9d means an acyl group derived from heterocyclyl-Oxe2x80x94COOH wherein heterocyclyl is as defined above. The term xe2x80x9cheterocyclylalkanoylxe2x80x9d means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclylalkoxycarbonylxe2x80x9d means an acyl radical derived from heterocyclyl-substituted alkane-Oxe2x80x94COOH wherein heterocyclyl has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acylradical derived from a carboxylic acid represented by heteroaryl-Oxe2x80x94COOH wherein heteroaryl has the significance given above.
The term xe2x80x9caminocarbonylxe2x80x9d alone or in combination, means an amino-substituted carbonyl(carbamoyl) group derived from an amino-substituted carboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group continuing substituents selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. The term xe2x80x9caminoalkanoylxe2x80x9d means an acyl radical derived from an amino substituted alkanecarboxylic acid wherein the amino group can be a primary, secondary or tertiary amino group containing substituents selected from the group consisting of hydrogen, cycloalkyl, cycloalkylalkyl radicals and the like, examples of which include N, N-dimethylaminoacetyl and N-benzylaminoacetyl. The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine. The term xe2x80x9cleaving groupxe2x80x9d generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, xe2x80x94OR and xe2x80x94SR and the like. Preferred leaving groups are indicated herein where appropriate. The term xe2x80x9cN-heterocyclic moietyxe2x80x9d is a heterocyclic radical with a nitrogen radical bond site which may be a heterocycloalkyl or heteroaryl, wherein heterocycloalkyl and heteroaryl have the significance given above, with the addition that polycyclic heteroaryl may be fully aromatic or partially aromatic, for example, a fused heterocycloalkylaryl and a fused heteroarylcycloalkyl, and heterocycloalkyl and cycloalkyl may also be bridged. Preferably, the N-heterocyclic moiety has 5, 6 or 7 members when monocyclic; 5, 6 or 7 members in a ring with 1, 2 or 3 members in a bridge when a bridged monocyclic; 11, 12 or 13 members when bicyclic; and 11 to 16 members when tricyclic.
Examples of N-heterocyclic moieties include, but are not limited to, those represented by the following formulas: 
wherein:
R20 represents hydrogen, alkyl, alkoxycarbonyl, monoalkylcarbamoyl, monoaralkylcarbamoyl, monoarylcarbamoyl or a group of the formula:
wherein:
R10 and R11 each represents alkyl;
R12 represents hydrogen, hydroxy, alkoxycarbonylamino or acylamino;
R13 represents hydrogen, alkyl, aryl, alkoxycarbonyl or acyl;
m is 1, 2, 3, or 4;
p is 1 or 2; and
r is independently 0, 1 or 2.
Procedures for preparing the compounds of Formulas I, II, III, IV, V and VI are set forth below. It should be noted that the general Procedure is shown as it relates to preparation of compounds having the specified stereochemistry, for example, wherein the stereochemistry about the hydroxy group is designated as (R). However, such procedures are generally applicable to those compounds of opposite configuration, e.g., where the stereochemistry about the hydroxyl group is (S). The terms (R) and (S) configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure appl. Chem. (1976)45, 13-30.
Likewise, procedures to obtain the preferred stereochemistry and its opposite configuration for the carbon to which R48 is attached, and particularly when R48 is hydrogen, are generally applicable from that disclosed in Example 4 below.
Preparation of Compounds of Formula I, III, IV, V and VI
Preparation of the compounds of Formula I are accomplished by preparing a cyclic sulfone carboxylic acid according to the following Scheme 1 and Scheme 1a: 
Exemplary conditions for the preparation of Scheme 1 are found in Preparation 1 hereinafter. For a cyclic sulfone having a seven membered ring the corresponding starting material may be substituted using analogous reaction conditions. On the other hand, for a cyclic sulfone having a five membered ring, the known starting material, 3-methoxy-carbonyl-2,5-dihydrothiophene-1,1-dioxide is hydrogenated and deesterified in a manner analogous to the last two steps shown in Scheme 1 and exemplified in Preparation 2 hereinafter.
A urea isostere of the formula A, the formula B, or the formula C that is prepared according to the methods of PCT Number WO-PCT/US92/8613 or PCT Application Number PCT/US92/08700, and PCT/US91/8593, respectively, which are incorporated by reference therefor, is then coupled with the cyclic sulfone carboxylic acid prepared above to obtain the compound of the formula I or VI in the manner set out in Scheme 2 hereinafter: 
Suitable coupling agents are well-known in the art and include dicyclohexylcarbodiimide or diisopropylcarbodiimide. The coupling is conducted at a temperature of from 20xc2x0 C. to about 50xc2x0 C., preferably at about 25xc2x0 C., in a suitable solvent system such as, for example, N,N-dimethylformamide, and the like. The amino protecting groups are those known in the art and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyl and the like, preferable carbobenzoxy and t-butoxycarbonyl.
Preparation of the Compounds of Formula II
The cyclic sulfone carboxylic acid is again prepared as set out above in Scheme 1.
An amino epoxide, which is a mixture of diastereomers of the corresponding amino-protected epoxides of the formulas: 
is prepared by the processes shown in patent application Ser. No. PCT/US91/8617 and is incorporated by reference therefor. P1 and P2 independently represent hydrogen and amino-protection groups well known in the art and include carbobenzoxy, butyryl, t-butoxycarbonyl, acetyl, benzoyl and the like, preferably carbobenzoxy and t-butoxycarbonyl, acetyl, benzoyl and the like, preferably carbobenzoxy and t-butoxycarbonyl; and R2 represents a radical as set out above. These diastereomers can be separated by chromatography or; alternatively, once reacted in subsequent steps the diastereomeric products can be separated.
The amino epoxide is then reacted, in a suitable solvent system, with an equal amount, of the formula:
HNR4xe2x80x2R5xe2x80x2
wherein R4xe2x80x2 and R5xe2x80x2 are as defined above. The reaction can be conducted over a wide range of temperatures, e.g., from about 60 C to about 120 C in an inert organic solvent, but is preferably, but not necessarily, conducted at a temperature at which the solvent begins to reflux. Suitable solvent systems include those wherein the solvent is an alcohol, such as methanol, ethanol, isopropanol, and the like, ethers such as tetrahydrofuran, dionane and the like, toluene, N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. A preferred solvent is isopropanol. Examples of amines corresponding to the formula HNR4xe2x80x2R5xe2x80x2 include those having the following formula: 
wherein R20, R10, R11, R12, R13, m, p an d r have the significance given above, and the like. The resulting product is a 3-(N-protected amino)-3-(R2)-1-NR4R5-propan-2-ol derivative (hereinafter referred to as an amino alcohol) is an intermediate which contains the desired N-heterocyclic moiety or intermediate thereof and can be represented by the formula: 
wherein P1, P2, R2, R4xe2x80x2 and R5xe2x80x2 are as described above.
Alternatively, the compounds of the present invention represented by Formula II above can be prepared utilizing the following general procedure. An N-protected haloketone derivative of an amino acid; also prepared by methods in patent application Ser. No. PCT/US91/8617 and incorporated by reference therefor, having the formula: 
wherein P1 and P2 represent amino protecting groups, R2 is as defined above, and Z represents a chlorine, bromine or iodine atom, is reacted, in a suitable inert organic solvent system, with an equal amount of a desired amine of the formula:
HNR4xe2x80x2R5xe2x80x2
wherein R4xe2x80x2 and R5xe2x80x2 are as defined above. The reaction yields a compound of the general formula(5): 
wherein P1, P2, R2, R4xe2x80x2 and R5xe2x80x2 have the significance given earlier.
The reaction of the N-protected haloketone derivative of an amino acid, preferably one in which P1 and P2 represent benzyloxy carbonyl, with the desired amine, a heterocyclic compound of formula HNR4R5, can be carried out in any known manner, for example, in an inert organic solvent such as halogenated aliphatic hydrocarbon (e.g., dichloromethane, N,N-dimethylformamide, tetrahydrofuran, isopropanol and ethanol) and in the presence of a base (e.g., a trialkylamine such as triethylamine and diisopropylethyl amine, sodium bicarbonate, DBU and the like, conveniently at about room temperature.
The reduction of the aminoketone compound of Formula 5 results in a compound of the general formula (6): 
wherein P1, P2, R2, R4 and Rxe2x80x25xe2x80x2 have the significance given earlier. The reduction of the aminoketone compound of Formula 5 to the N-heterocyclic moiety-containing derivative (Formula VI) can be carried out according to known methods for the reduction of a carbonyl group to a hydroxy group. Thus, for example, the reduction can be carried out using a complex metal hydride such as an alkali metal borohydride, especially sodium borohydride, in an appropriate organic solvent such as alkanol (e.g., methanol, ethanol, propanol, isopropanol, etc.). Conveniently, the reduction is carried out at about room temperature.
Then this N-heterocyclic moiety-containing derivative having an amino protecting group P is or P1 and P2 are, removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of the protecting group, e.g., removal of a carbobenzoxy group, by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. Where the protecting group is N,N-dibenzyl, these groups may be removed by hydrogenolysis utilizing palladium on carbon.
Where the protecting group is a t-butoxycarbonyl group, it can be removed utilizing an inorganic or organic acid, e.g., HCl or trifluoroacetic acid, in a suitable solvent system, e.g., dioxane or methylene chloride. The resulting product is the amine salt derivative.
Following neutralization of the salt, the amine is then reacted with a cyclic sulfone carboxylic acid as prepared above to produce the antiviral compounds of the present invention having the formula II also as defined above. The reaction of the amine with a cyclic sulfone carboxylic acid is as shown in the following Scheme 3:
Conditions of the Scheme 3 are generally as follows. The cyclic sulfone carboxylic acid can be coupled to any of the desired isosteres using methods well known to those in the art. For example, activation of the acid can be accomplished using dicyclocarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of N-hydroxybenzotriazole in a suitable solvent, such as N,N-dimethylformamide, tetrahydrofuran or methylene chloride. Alternately, the acid can be activated by treatment with N,N-disuccinimidyl carbonate and pyridine. The resulting active esters can then be reacted with the desired isostere, optionally with a base (such as diisopropylethylamine) present, to afford the desired cyclic sulfone containing retroviral protease inhibitors.
The R6 substituent is then added according to the analogous procedures also described in PCT/US91/8613 and WO9208700, incorporated by reference therefor.
Finally, an amino alcohol is prepared by reacting the amino epoxide described above or a corresponding haloalcohol with R3NH2 also in a manner described in U.S. patent application Ser. No. PCT/US91/8617 incorporated by reference therefor to obtain the compound of the formula: 
wherein P, R2 and R3 are as defined above.
The amino alcohol defined above is then reacted in a suitable solvent with a sulfonyl chloride (R4SO2Cl) or sulfonyl anhydride in the presence of an acid scavenger. Suitable solvents in which the reaction can be conducted include methylene chloride, tetrahydrofuran and the like. Suitable acid scavengers include triethylamine, pyridine and the like. Preferred sulfonyl chlorides are methanesulfonyl chloride and benzenesulfonyl chloride. The resulting sulfonamide derivative can be represented, depending on the epoxide utilized by the formulas: 
wherein P, P1, P2, R2, R3 and R4xe2x80x3 are as defined above.
The sulfonyl halides of the formula R4xe2x80x3SO2X can be prepared by the reaction of a suitable Grignard or alkyl lithium reagent with sulfuryl chloride, or sulfur dioxide followed by oxidation with a halogen, preferably chlorine. Also, thiols may be oxidized to sulfonyl chlorides using chlorine in the presence of water under carefully controlled conditions. Additionally, sulfonic acids may be converted to sulfonyl halides using reagents such as PCl5, and also to anhydrides using suitable dehydrating reagents. The sulfonic acids may in turn be prepared using procedures well known in the art. Such sulfonic acids are also commercially available. In place of the sulfonyl halides, sulfinyl halides (R4SOX) or sulfenyl halides (R4SX) can be utilized to prepare compounds wherein the xe2x80x94SO2xe2x80x94 moiety is replaced by an xe2x80x94SOxe2x80x94 or xe2x80x94Sxe2x80x94 moiety, respectively.
A cyclic sulfone of the formula Ixe2x80x2 wherein Q is represented by (4) or (5) above is prepared in a like manner.
For example, an intermediate, the amino alcohol, is reacted as shown in the following Scheme 3A. 
In other words, the amino alcohol defined above is then reacted in a suitable solvent with a sulfamoyl halide, e.g., sulfamoyl chloride (R4R5NSO2Cl or R4HNSO2Cl) or corresponding sulfanoyl anhydride in the presence of an acid scavenger. Suitable solvents in which the reaction can be conducted include methylene chloride, tetrahydrofuran. Suitable acid scavengers include triethylamine, pyridine. The resulting sulfamic acid derivative can be represented, depending on the epoxide utilized, by the formulas: 
wherein P, P1, P2, R2, R3, R4 and R5 are as defined above. These intermediates are useful for preparing inhibitor compounds of the present invention and are also active inhibitors of retroviral proteases.
The sulfamoyl halides of the formula R4NHSO2X can be prepared by the reaction of a suitable isocyanate of the formula R4NCO with fuming sulfuric acid to produce the corresponding sulfamate which is then converted to the halide by well known procedures, such as by treating the sulfamate with PCl5. Alternatively, the isocyanate can be treated with chlorosulfonic acid to produce the corresponding sulfamoyl chloride directly.
The sulfamoyl halides of the formula R4R5NSO2Cl can be prepared by reacting an amine of the formula R4R5NH, preferably as a salt such as the hydrochloride, with sulfuryl chloride in a suitable solvent such as acetonitrile. The reaction mixture is gradually warmed to reflux temperature and maintained at the reflux temperature until the reaction is complete. Alternatively, sulfamoyl halides of the formula R4R5NSO2Cl can be prepared by reacting an amine of the formula R4R5NH with sulfuryl chloride in boiling MeCN as disclosed in Matier et al., J. Med. Chem., 15, No.5, p. 538 (1972).
In an analogous manner a sulfamoyl halide, preferably Cl, of the formula: 
is reacted with the amino alcohol as defined above.
Following preparation of the sulfonamide derivative, the amino protecting group P or p1 and p2 is removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of the protecting group, e.g., removal of a carbobenzoxy group, by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. Where the protecting group is a t-butoxycarbonyl group, it can be removed utilizing an inorganic or organic acid, e.g., HCl or trifluoroacetic acid, in a suitable solvent system, e.g., dioxane or methylene chloride. The resulting product is the amine salt derivative. Where the protecting group is a benzyl radical, it an b removed by hydrogenolysis. Following neutralization of the salt, the amine, D, E or F, is then reacted with a cyclic sulfone as described below and shown as follows: 
wherein R2, R3, R4xe2x80x3 and q is as defined above.
The conditions of the reaction in Scheme 4 include suitable solvent systems, such as, generally, recited following Scheme 3 above.
In order to prepare the tetrahydrothiopyran-4-carboxamide sulfone and its analogs, one can start from the commercially available tetrahydrothiopyran-4-one (compound 1 in Scheme 5). The ketone 1 can be reduced to the alcohol 2 using a variety of methods including sodium borohydride or lithium aluminum hydride. The alcohol can then be converted into a leaving group X, such as chloro, bromo, iodo, O-methanesulfonate, or O-p-toluenesulfonate, of the like. The leaving group X is then displaced with a cyanide source, such as sodium cyanide, potassium cyanide, lithium cyanide or tetra-n-butylammonium cyanide, in a suitable solvent, such as dimethyl sulfoxide, N,N-dimethylformamide or N-methylpyrrolidinone, to provide the cyanide 4. The cyano group can then be hydrolyzed under a variety of conditions well known to those skilled in the art. The hydrolysis to the acid 6 can either be accomplished directly in one step or using a two step procedure involving the amide 5. Thus the cyano compound 4 can be converted to the amide 5 using concentrated sulfuric acid, and the amide converted to the acid using sodium hydroxide or potassium hydroxide in aqueous methanol or ethanol. Alternatively, the cyano compound 4 can be directly hydrolyzed to the acid 6-using concentrated hydrochloric acid at reflux. The sulfur in acid 6 can then be oxidized to the sulfone by various methods, such as, meta-chloroperbenzoic acid, sodium perborate in acetic acid, or hydrogen peroxide in acetic acid, using greater than two equivalents of oxidizing agent. If one desires the sulfoxide, rather than the sulfone, one can use one equivalent of oxidizing agent. The acids 6 and 7 can readily be converted to the compounds of this invention by reaction with various isosteres using standard coupling techniques. It is envisioned that through appropriate modifications of the sequence of reactions in Scheme 5, a variety of analogs can be made with substituents on the tetrahydrothiopyran ring. 
Further, a compound of the present invention wherein W is a heterocyclic ring having a substituent other than hydrogen represented as R40, R41, R42, R43, R44, R45, R46, R47 or R48 can be prepared by the method and Scheme showing the method in the following manner.
In order to prepare the thiomorpholine analog of the cyclic sulfone, as shown in Scheme 6, one can start with either D-, L-, or D,L-cysteine. Reaction of cysteine or an ester of cysteine (compound 8, Scheme 6), where R1 is hydrogen, methyl, ethyl, t-butyl, benzyl or other carboxyl protecting groups with a species Xxe2x80x94CKH2CO2R2, where X is a leaving group as defined above and R2 is independently hydrogen, methyl, ethyl, t-butyl, benzyl or other carboxyl protecting groups, in the presence of a base such as sodium bicarbonate, triethylamine, or the like provides the cyclic sulfide 9. The sulfide 9 can then be oxidized to either the sulfoxide or sulfone using the methods described above. If necessary, the carboxyl protecting group can be removed from 9 or 10 and the resulting carboxylic acid coupled to the various isosteres using standard methods. It is also envisioned that one could use D-, L- or D less than L-penicillamine [HSC(CH3)2CH(NH2)CO2H] in place of cysteine 8. It is also contemplated that appropriate modifications of the sequence would provide a variety of analogs. 
For compounds wherein the oxidation state of the cyclic sulfur in the W substituent is within that of the desired product, the oxidation of Schemes 1 and 1a can be performed with a suitable oxidizing agent; such as hydrogen peroxide, sodium perborate or meta-chloroperbenzoic acid. It is well known to those skilled in the art that this oxidation can be cotrolled through the use of one equivalent of oxidizing agent to provide the sulfoxide or at least two or more equivalents to provide the the sulfone.
Where a substituent is designated as, or can be, a hydrogen, the exact chemical nature of a substituent which is other than hydrogen at that position, e.g., a hydrocarbyl radical or a halogen, hydroxy, amino and the like functional group, is not critical so long as it does not adversely affect the overall activity and/or synthesis procedure.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable form known starting materials.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the following examples, melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected. All reagents were used as received without purification. All proton and carbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400 nuclear magnetic resonance spectrometer using tetramethylsilane as internal standard. Gas chromatograph was performed on a Varian 3400 chromatography system. All instruments were utilized according to the manufacturer""s directions.